Wermke et al. reported interim data from a phase 1 dose-escalation trial of IMA203 – PRAME-directed autologous TCR T cell therapy – in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors. Although the PRAME TCR was pairing-optimized and affinity-enhanced, IMA203 was safe and well tolerated, without any treatment-related fatalities. IMA203 rapidly engrafted tumors and demonstrated long-term persistence. In the 40 patients treated with IMA203, the unconfirmed/confirmed (u/c)ORR was 52.5%, and the cORR was 28.9%, with a median duration of response of 4.4 months. Higher PRAME expression and T cell infiltration correlated with deeper responses and longer PFS.
Contributed by Shishir Pant
ABSTRACT: In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3_+_3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02(+) patients with PRAME(+) recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4_months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 .
Author Info: (1) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. National Center for Tumor Diseases, Dresden, Germany. (2) Department of Sarcoma Me
Author Info: (1) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. National Center for Tumor Diseases, Dresden, Germany. (2) Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Comprehensive Cancer Center Mainfranken, University Hospital Wrzburg, Wrzburg, Germany. (4) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Hematology, Oncology, Immunooncology, Stem Cell Transplantation, and Rheumatology, University Hospital Bonn, Bonn, Germany. (6) Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Columbia University Medical Center, New York, NY, USA. (8) Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (9) Department of Oncology, Hematology, and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (10) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. (11) Department of Hematology, Oncology, Immunooncology, Stem Cell Transplantation, and Rheumatology, University Hospital Bonn, Bonn, Germany. (12) Immatics Biotechnologies GmbH, Tbingen, Germany. (13) Immatics Biotechnologies GmbH, Tbingen, Germany. (14) Immatics Biotechnologies GmbH, Tbingen, Germany. (15) Immatics Biotechnologies GmbH, Tbingen, Germany. (16) Immatics Biotechnologies GmbH, Tbingen, Germany. (17) Immatics Biotechnologies GmbH, Tbingen, Germany. (18) Immatics Biotechnologies GmbH, Tbingen, Germany. (19) Immatics US, Inc., Houston, TX, USA. (20) Immatics Biotechnologies GmbH, Tbingen, Germany. (21) Immatics US, Inc., Houston, TX, USA. (22) Immatics US, Inc., Houston, TX, USA. (23) Immatics Biotechnologies GmbH, Tbingen, Germany. (24) Immatics Biotechnologies GmbH, Tbingen, Germany. (25) Immatics Biotechnologies GmbH, Tbingen, Germany. (26) Immatics Biotechnologies GmbH, Tbingen, Germany. (27) Immatics US, Inc., Houston, TX, USA. (28) Immatics US, Inc., Houston, TX, USA. (29) Immatics US, Inc., Houston, TX, USA. (30) Immatics Biotechnologies GmbH, Tbingen, Germany. (31) Immatics Biotechnologies GmbH, Tbingen, Germany. (32) Immatics Biotechnologies GmbH, Tbingen, Germany. (33) Immatics Biotechnologies GmbH, Tbingen, Germany. (34) Institute of Immunology, Eberhard Karls University Tbingen, Tbingen, Germany. (35) Immatics Biotechnologies GmbH, Tbingen, Germany. (36) Immatics Biotechnologies GmbH, Tbingen, Germany. (37) Immatics US, Inc., Houston, TX, USA. (38) Immatics Biotechnologies GmbH, Tbingen, Germany. (39) Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (40) Immatics Biotechnologies GmbH, Tbingen, Germany. cedrik.britten@immatics.com.
